Crowned Dendrimers: pH-Responsive Pseudorotaxane Formation

Crowned Dendrimers: pH-Responsive Pseudorotaxane Formation Jason W. Jones,† William S. Bryant,† Anton W. Bosman,‡ Rene A. J. Janssen,‡ E. W. Meijer,‡ and Harry W. Gibson*,† Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, 24061-0212, and the Laboratorium of Macromolecular and Organic Chemistry, Eindhoven University of Technology, 5600 MB Eindhoven, The Netherlands [email protected] Received October 17, 2002

With the end goal of incorporating the unique structural and physical properties of dendrimers into supramolecular assemblies, bis(m-phenylene)-32-crown-10-functionalized poly(propyleneimine) dendrimers of the first and third generations have been synthesized and their interaction with paraquat diol has been investigated. Using 1H NMR, we determined that binding to the 4 or 16 crown ether sites occurred in an anti-cooperative fashion, most likely a result of steric influences. Upon protonation of the tertiary amines in the dendritic interior, binding became independent, i.e., statistical, and the average apparent association constant increased by nearly 5-fold; this effect is attributed to rigidification of the dendrimer, which makes its binding sites more accessible and less crowded. Introduction Among the many great contemporary areas of interest, dendritic and supramolecular chemistries have proven particularly appealing to the materials scientist. Whereas the ideal dendrimer is controlled synthetically as a monodisperse macromolecule with regularly branched three-dimensional architecture,1 the ideal supramolecular entity is controlled at the molecular level via thermodynamic equilibrium considerations.2 Recent efforts in the dendritic arena have focused on the dendrimer’s unique topology, which combines a high †

Virginia Polytechnic Institute and State University. Eindhoven University of Technology. (1) (a) Newkome, G. R.; Moorefield, C. N.; Vo¨gtle, F. Dendritic Molecules: Concepts, Syntheses and Perspectives; VCH Publishers: New York, 1996. (b) Newkome, G. R.; He, E.; Moorefield, C. N. Chem. Rev. 1999, 99, 1689-1746. (c) Bosman, A. W. Janssen, H. M.; Meijer, E. W. Chem. Rev. 1999, 99, 1665-1688. (d) Froehling, P. E. Dyes Pigm. 2001, 48, 187-195. (e) Dendrimers and Other Dendritic Polymers, Fre´chet, J. M. J.; Tomalia, D. A., Eds., John Wiley and Sons: New York, 2001. (2) (a) Comprehensive Supramolecular Chemistry, Atwood, J. L.; Davies, J. E. D.; MacNicol, D. D.; Vo¨gtle, F., exec. Eds., Pergamon Press: New York, 1996. (b) Steed, J. W.; Atwood, J. L. Supramolecular Chemistry; J. Wiley and Sons: New York, 2000. (c) Brunsveld, L.; Folmer, B. J. B.; Meijer, E. W.; Sijbesma, R. P. Chem. Rev. 2001, 101, 4071-4098. (3) (a) Groehn, F.; Bauer, B. J.; Amis, E. J. Macromolecules 2001, 34, 6701-6707. (b) Christensen, J. B.; Nielsen, M. F.; Van Haare, J. A. E. H.; Baars, M. W. P. L.; Janssen, R. A. J.; Meijer, E. W. Eur. J. Org. Chem. 2001, 11, 2123-2128. (c) Dykes, G. M. J. Chem. Technol. Biotechnol. 2001, 76, 903-918. (d) Sadler, K.; Tam, J. P. Rev. Mol. Biotechnol. 2002, 90, 195-229. (4) (a) Molecular Catenanes, Rotaxanes and Knots: A Journey Through the World of Molecular Topology; Sauvage, J.-P., DietrichBuchecker, C., Eds.; Wiley-VCH: Weinheim, 1999. (b) Gibson, H. W.; Mahan, E. J. in Cyclic Polymers, 2nd ed.; Semlyen, J. A., Ed.; Kluwer Academic Publishers: Dordrecht, 2000; pp 415-560. (c) Hubin, T. J.; Busch, D. H. Coord. Chem. Rev. 2000, 200-202; 5-52. (d) Panova, I. G.; Topchieva, I. N. Russ. Chem. Rev. 2001, 70, 23-44. ‡

local density of active groups with a discrete number of functional groups.1,3 Additional novel architectures such as rotaxanes and catenanes4 have evolved independently, beginning with Frisch and Wasserman’s preparation of physically interlocked rings over 40 years ago.5 Of interest is the use of rotaxanes as templates in the construction of novel recognition motifs, particularly for the formation of supramolecular dendritic arrays assembled via crown ether cores.6 Although such hostguest systems based on dendrimers abound in the literature,7 few utilize recognition motifs at the periphery of the dendritic molecule.8 We here report on the preparation of pseudorotaxane9 functionalized dendrimers,10 fashioned from first and third generation poly(propyleneimine) (PPI) dendrimers1c end-capped with bis(m-phenylene)-32-crown-10 (5) Frisch, H. L.; Wasserman, E. Am. Chem. Soc., Div. Polymer Chem., Preprints 1960, 1, 93-97. (6) (a) Percec, V.; Johansson, G.; Ungar, G.; Zhou, J. P. J. Am. Chem. Soc. 1996, 118, 9855-9866. (b) Yamaguchi, N.; Hamilton, L. M.; Gibson, H. W. Angew. Chem., Int. Ed. 1998, 37, 3275-3279. (c) Osswald, F.; Vogel, E.; Safarowsky, O.; Schwanke, F.; Vo¨gtle, F. Adv. Synth. Catal. 2001, 343, 303-309. (d) Gibson, H. W.; Yamaguchi, N.; Hamilton, L.; Jones, J. W. J. Am. Chem. Soc. 2002, 124, 4653-4665. (7) (a) Zimmerman, S. C.; Wendland, M. S.; Rakow, N. A.; Zharov, I.; Suslick, K. S. Nature 2002, 418, 399-403. (b) Newkome, G. R.; Cho, T. J.; Moorefield, C. N.; Cush, R.; Russo, P. S.; Godinez, L. A.; Saunders: M. J.; Mohapatra, P. Chem. Eur. J. 2002, 8, 2946-2954. (c) Diederich, F.; Felber, B. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 4778-4781. (8) (a) Michels, J. J.; Baars, M. W. P. L.; Miejer, E. W.; Huskens, J.; Reinhoudt, D. N. J. Chem. Soc., Perkin Trans. 2 2000, 1914-1918. (b) Zhou, M.; Roovers, J. Macromolecules 2001, 34, 244-252. (c) Lee, J. W.; Ko, Y. H.; Park, S.-H.; Yamaguchi, K.; Kim, K. Angew. Chem., Int. Ed. 2001, 40, 746-749. (d) De Groot, D.; de Waal, B. F. M.; Reek, J. N. H.; Schenning, A. P. H. J.; Kamer, P. C. J.; Meijer, E. W.; van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2001, 123, 8453-8458. (e) Dam, T. K.; Roy, R.; Page´, D.; Brewer, C. F. Biochemistry 2002, 41, 1359-1363. (f) Alonso, B.; Casado, C. M.; Cuadrado, I.; Moran, M.; Kaifer, A. E. Chem. Commun. 2002, 16, 1778-1779.

10.1021/jo0265784 CCC: $25.00 © 2003 American Chemical Society

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(BMP32C10) host macrocycles and N,N′-bis(β-hydroxyethyl)-4,4′-bipyridinium bis(hexafluorophosphate) (paraquat diol).

SCHEME 2. Synthesis of Crowned PPI Dendrimers 6 and 7

Results and Discussion Synthesis of BMP32C10-Functionalized Dendrimers. Because the reaction between primary amines and succinimide esters is reportedly quantitative, even under mild conditions,11 we employed this method in a model surface functionalization by coupling the primary amine end groups of N-methyl-N,N-bis(3-aminopropyl)amine (1) with the succinimide ester (2) of 1,3-phenylene-16crown-5 to yield N-methyl-N,N-bis[N′-(5-carboxy-1,3phenylene-16-crown-5)propylamino]amine (3, Scheme 1) SCHEME 1. Preparation of Model Compounds for Formation of Crowned Dendrimers

with 100% conversion. Encouraged by these results, identical reactions were successfully conducted using the first, third, and fifth generation PPI dendrimers. To integrate such receptor-functionalized dendrimers into pseudorotaxane arrays, the larger succinimide ester (4) of dibenzo-24-crown-8 was reacted with 1 under identical conditions (Scheme 1); however, analysis showed incomplete conversion to N-methyl-N,N-bis[N′-(2-car(9) While we acknowledge the possibility that such a complex may adopt a folded or “taco” structure in solution [(a) Bryant, W. S.; Guzei, I. A.; Rheingold, A. L.; Gibson, H. W. Org. Lett. 1999, 1, 47-50. (b) Jones, J. W.; Zakharov, L. N.; Rheingold, A. L.; Gibson, H. W. J. Am. Chem. Soc. 2002, 124, 13378-13379], we choose to refer to the BMP32C10/paraquat complex as a pseudorotaxane, which must exist in light of the fact that catenanes have been prepared using this motif [Amabilino, D. B.; Anelli, P.-L.; Ashton, P. R.; Brown, G. R.; Cordova, E.; Godinez, L. A.; Hayes, W.; Kaifer, A. E.; Philp, D.; Slawin, A. M. Z.; Spencer, N.; Stoddart, J. F.; Tolley, M. S.; Williams, D. J. J. Am. Chem. Soc. 1995, 117, 11142-11170]. (10) (a) Gibson, H. W.; Bosman, A. W.; Bryant, W. S.; Jones, J. W.; Jannsen, R. A. J.; Meijer, E. W. Polym. Mater. Sci. Eng. 2001, 84, 6667. (b) Stephan, H.; Spies, H.; Johannsen, B.; Gloe, K.; Gorka, M.; Vo¨gtle, F. Eur. J. Inorg. Chem. 2001, 2957-2963. (11) Bailey, P. D.; Collier, I. D.; Morgan, K. M. Comprehensive Organic Functional Group Transformations; Moody, C. J., Ed.; Elsevier Science, Ltd.: Tarrytown, NY, 1995; Vol. 5, pp 257-307.

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boxydibenzo-24-crown-8)propylamino]amine (5). The functionalization of the first generation PPI dendrimer with 4 was also attempted, again resulting in incomplete conversion of the endgroups. We therefore converted the primary amine end groups of the dendrimers into isocyanates,12 followed by in situ coupling to 5-hydroxymethyl-1,3-phenylene-1,3-phenylene32-crown-1013 (Scheme 2), yielding “crowned” PPI dendrimers 6 and 7, in excellent yields. Complexation of Neutral BMP32C10-Functionalized Dendrimers with Paraquat Diol. The BMP32C10functionalized dendrimers were designed to be polyfunctional hosts for paraquat derivatives, as depicted in Scheme 3, leading sequentially to [2]-, [3]-, etc. pseudorotaxanes. A priori the relative values of the binding constants K for the sequential steps can (a) decrease statistically, (b) decrease more strongly than statistically predicted in an anti-cooperative manner or (c) decrease less than statistically predicted (or even increase) in a cooperative manner.14 Titration was employed to study the binding behavior of 6 and 7 with paraquat diol (8-2PF6) using 1H NMR spectroscopy in acetone-d6 at 21.8 °C and a constant crown end group concentration of 3.0 mM. Upon mixing the host and guest components, a bright orange-colored solution resulted, indicating rapid complex formation via (12) (a) Peerlings, H. W. I.; Meijer, E. W. Tetrahedron Lett. 1999, 40, 1021-1024. (b) Versteegen, R. M.; Sijbesma, R. P.; Meijer, E. W. Angew. Chem., Int. Ed. 1999, 38, 2917-2919. (13) Gibson, H. W.; Nagvekar, D. S.; Yamaguchi, N.; Wang, F.; Bryant, W. S. J. Org. Chem. 1997, 62, 4798-4803. (14) (a) Marshall, A. G. Biophysical Chemistry; Wiley: New York, 1978; Chapter 3. (b) Conners, K. A. Binding Constants; Wiley: New York, 1987; pp 46-86. (c) Attie, A. D.; Raines, R. T. J. Chem. Educ. 1995, 72, 119-124.

pH-Responsive Pseudorotaxane Formation SCHEME 3. Representation of the Complexation of Monotopic Paraquat Diol (8-2PF6) by Complementary Polytopic Dendrimers 6 and 7, Showing the Sequential Formation of [2]-, [3]-, [4]-, etc. Pseudorotaxanes with Association Constants K1, K2, K3, etc.

hydrogen bonding and π-stacking interactions of host and guest.15 Indeed, the time-averaged signals of Ha and Hb of the crown ether moiety were shifted upfield relative to those of pure 6 or 7 upon complexation with 8-2PF6. MALDI-TOF MS of the first generation dendrimer in the presence of 4 equiv of paraquat dihexafluorophosphate (9-2PF6) also confirmed complex formation, showing a peak at m/z 3492 attributable to the [3]pseudorotaxane {[6‚(9-2PF6)2 - PF6]+}.

FIGURE 1. Scatchard plots for the binding of 6 (0) and 7 (b) with 8-2PF6 in acetone-d6 at 21.8 °C and a constant crown end group concentration of 3.0 mM, based on Ha.17

To analyze the chemical shift data, ∆0, the difference in δ values for the aromatic protons of the uncomplexed and fully complexed crown ether, was assumed to be equivalent to that for the model system of bis(5-acetoxy1,3-phenylene)-32-crown-10 (10) and 8-2PF6.16 The fraction of total binding sites occupied, θ, and the equilibrium guest concentration, [8-2PF6]uc, were then estimated. Scatchard plots (Figure 1) are nonlinear for both the first (6) and third (7) generation crowned dendrimers, indicating that the binding is dependent upon neighboring occupied host moieties;14 the concave slopes indicate anticooperative binding. Consequently, the data were interpreted using the Hill equation.14c For both generations the Hill coefficient (i.e., the slope) is less than unity (Figure 2), indicating that binding is anti-cooperative: from the intercepts we determine KAVE ) 23 ( 3 M-1 for 6 and KAVE ) 15 ( 2 M-1 for 7, values which are substantially lower than apparent Ka (15) (a) Allwood, B. L.; Spencer, N.; Sharhriari-Zavareh, H.; Stoddart, J. F.; Williams, D. J. J. Chem. Soc., Chem. Commun. 1987, 10581061. (b) Gillard, R. E.; Raymo, F. M.; Stoddart, J. F. Chem. Eur. J. 1997, 3, 1933-1940. (c) Asakawa, M.; Ashton, P. R.; Dehaen, W.; L’abbe, G.; Menzer, S.; Nouwen, J.; Raymo, F. M.; Stoddart, J. F.; Tolley, M. S. Chem. Eur. J. 1997, 3, 772-787. (d) Raymo, F. M.; Bartberger, M. D.; Houk, K. N.; Stoddart, J. F. J. Am. Chem. Soc. 2001, 123, 9264-9267. (16) Gong, C.; Balanda, P. B.; Gibson, H. W. Macromolecules 1998, 31, 5278-5289. ∆0, the average value determined by the BenesiHildebrand, Scatchard, and Creswell-Allred plotting techniques, was 0.543 ppm.

FIGURE 2. Hill plots for the binding of 6 (0) and 7 (b) with 8-2PF6 in acetone-d6 at 21.8 °C, based on Ha.17

) 61 ( 5 M-1 for the model system 11/8-2PF6 under these conditions. In addition, as can be seen from Figure 2, binding of 8-2PF6 is facilitated in 6 relative to 7. This finding is not unexpected: theoretical calculations18 as well as small-angle neutron-scattering studies19 indicate that the importance of backfolding in PPI dendrimers increases with generation; intramolecular H-bonding of the CON-H moieties to the amine moieties may also be a factor. Furthermore, electrostatic repulsions among neighboring guest ions at the periphery of the larger (17) To determine error bars, we assumed an inaccuracy of (5.0% in ∆0 and calculated high and low values for θ, [8-2PF6]uc, and θ/[82PF]uc about this range. (18) Murat, M.; Grest, G. S. Macromolecules 1996, 29, 1278-1285. (19) (a) Scherrenberg, R.; Coussens, B.; van Vliet, P.; Edouard, G.; Brackman, J.; de Brabander, E.; Mortensen, K. Macromolecules 1998, 31, 815-822. (b) Poetschke, D.; Ballauff, M.; Lindner, P.; Fischer, M.; Vo¨gtle, F. Macromolecules 1999, 32, 4079-4087. (c) Poetschke, D.; Ballauff, M.; Lindner, P.; Fischer, M.; Vo¨gtle, F. Macromol. Chem. Phys. 2000, 201, 330-339. (d) Poetschke, D.; Ballauff, M.; Lindner, P.; Fischer, M.; Vo¨gtle, F. J. Appl. Crystallogr. 2000, 33, 605-608.

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FIGURE 3. Scatchard plot for the binding of protonated 7-H+ with 8-2PF6 in acetone-d6 at 21.8 °C, based on Ha, [TFA-] ) 2.62 mM (0.875 equiv relative to BMP32C10 moieties).17

FIGURE 4. 1H NMR spectra (400 MHz, acetone-d6, 22.6 °C)

crown ether functionalized dendrimer 7 may result in less efficient binding than for dendrimer 6. Complexation of Protonated BMP32C10-Functionalized Dendrimers with Paraquat Diol. The influence of folding on the nature of host/guest interaction was tested by protonation of the tertiary amines of the dendritic framework via addition of an equivalent amount of trifluoroacetic acid. A Scatchard plot for 7-H+/8 (Figure 3, [end group] ) 3.0 mM) is linear, indicating independence of binding sites; the slope and intercept yield an average apparent association constant of 70 ( 8 M-1, which represents a 4.7-fold increase in KAVE upon protonation. This value is within experimental error of apparent Ka ) 61 ( 5 M-1 for the model system 11/82PF6 under identical conditions. Effect of Trifluoroacetate Ions on a Model Complexation. To determine the impact of trifluoroacetate counteranions on the complexation, a model system consisting of BMP32C10 (11) complexed with 8-2PF6 was titrated with tetraethylammonium trifluoroacetate (12TFA).20 As we have previously observed in other systems,9b the addition of the trifluoroacetate salt hinders association of 11 with 8: the upfield shifted host aromatic protons observed upon complexation of 11 with 8-2PF6 shift downfield upon addition of 12-TFA (see Figure 4b vs 4c,d). Furthermore, the H1-H5 signals of 8 significantly broaden with increasing [12-TFA]. Again using ∆0 from our model system,16 we determine apparent Ka ) 35 ( 5 M-1 when 3.75 equiv of 12-TFA are present, a 43% reduction from 11/8-2PF6. Such a reduction in binding strength may be accounted for through counteranion exchange between the weakly paired PF6 salt and the more tightly paired TFA salt.21 Conclusions There exists an obvious “switch” in binding between unprotonated and protonated host macromolecules from an anti-cooperative regime to an independent one, despite the negative influence of added trifluoroacetate anion. Such a “switch” may be explained by rigidification of the protonated dendrimer in which the macromolecule is electrostatically forced to adopt a conformation that maximizes host binding site separation.22 Coupled with (20) The addition of tetraethylammonium trifluoroacetate to BMP32C10 (11) had no influence on the 1H NMR chemical shifts of 11. Thus, tetraethylammonium ion does not bind to 11. (21) Davies, K. M.; Whyte, K. D.; Gilbert, A. H. Inorg. Chimica Acta 1990, 177, 121-126.

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of (a) 11; (b) 3.05 mM 11 + 2.95 mM 8-2PF6; (c) 2.03 mM 11 + 1.97 mM 8-2PF6 + 2.50 mM 12-TFA; (d) 2.03 mM 11 + 1.97 mM 8-2PF6 + 7.50 mM 12-TFA. The asterisk denotes an impurity in 11 that is not involved in pseudorotaxane formation and is believed to be tetra(m-phenylene)-64-crown-20, a predicted byproduct of the cyclization reaction.

our recent report6d on cooperative23 binding of positively charged tritopic guest core molecules with hydrophobic host dendrons, the above work foreshadows systems in which the binding can be made to be highly cooperative and thus mimic the foundation of DNA chemistry, wherein conformational changes brought about through an initial binding interaction, i.e., allosteric effects,24 can serve to enhance or detract from the binding affinity of subsequent sites.25

Experimental Section Unless otherwise noted, the starting PPI dendrimers,1c crown ether macrocycles,13 and paraquat derivatives 826 and 915a were prepared according to published procedures. All other reagents were purchased from commercial suppliers and used without further purification. 1H NMR spectra were recorded on 300- or 400-MHz NMR spectrometers with the solvent proton signal as the reference and were collected immediately upon mixing the salt and crown solutions. To observe complex formation, a known volume of a specified concentration of crown macrocycle was added to an NMR tube. To these host solutions, measured volumes of a concentrated solution of salt were added and the tube was shaken vigorously for 30 s before data collection. N-(5-Carboxy-1,3-phenylene-16-crown-5)succinimide (2). 5-Carboxy-1,3-phenylene-16-crown-527 (2.087 g, 6.68 mmol) (22) Cationic branch repulsion has also been suggested: Kleinman, M, H.; Flory, J. H.; Tomalia, D. A.; Turro, N. J. J. Phys. Chem. B 2000, 104, 11472-11479. Mortensen et al. have confirmed that these dendrimers open up upon acidification: Ramzi, A.; Scherrenberg, R.; Brackman, J.; Joosten, J.; Mortensen, K. Macromolecules 1998, 31, 1621-1626. Others have shown rigidification upon inclusion of guest molecules: see ref 8a,c as well as (a) Jansen, J. F. G. A.; de Brabandervan den Berg, E. M. M.; Meijer, E. W. Science 1994, 265, 1226-1229. (b) Baars, M. W. P. L.; Karlsson, A. J.; Sorokin, V.; de Waal, B. F. W.; Meijer, E. W. Angew. Chem., Int. Ed. 2000, 39, 4262-4265. (23) See: Freifelder, D. M. Physical Biochemistry; W. H. Freeman and Co.: New York, 1982; pp 659-660. See also: Marshall, A. G. Biophysical Chemistry; Wiley: New York, 1978; pp 70-77. Conners, K. A. Binding Constants; Wiley: New York, 1987; pp 78-86. (24) See: Takeuchi, M.; Ikeda, M.; Sugasaki, A.; Shinkai, S. Acc. Chem. Res. 2001, 34, 865-873. (25) (a) Harris, S. A.; Gavathiotis, E.; Searle, M. S.; Orozco, M.; Laughton, C. A. J. Am. Chem. Soc. 2001, 123, 12658-12663. (b) Kissinger, C. R.; Liu, B.; Martin-Blanco, E.; Kornberg, T. B.; Pabo, C. O. Cell 1990, 63, 579-590. (26) Shen, Y. X.; Engen, P. T.; Berg, M. A. G.; Merola, J. S.; Gibson, H. W. Macromolecules 1992, 25, 2786-2788.

pH-Responsive Pseudorotaxane Formation and N-hydroxysuccinimide (0.792 g, 6.88 mmol) were dissolved in 30 mL of glyme. Dicyclohexylcarbodiimide (1.516 g, 7.35 mmol) was added, and the solution stirred for 24 h at 0 °C. The resultant white precipitate was filtered under vacuum, washed with CHCl3, and dried to yield an off-white oil. The oil was dissolved in hot isopropyl alcohol, and upon cooling a white powder was obtained, which was twice recrystallized from isopropyl alcohol. Yield: 2.36 g (86.2%). Mp ) 112.0115.3 °C. 1H NMR (CDCl3, 300 MHz, ambient T) δ (ppm): 7.43 (1H, m); 7.29 (2H, d, J ) 1.2 Hz); 4.33 (4H, m); 3.80 (4H, m); 3.62 (8H, m); 2.90 (4H, s). 13C NMR (DMSO-d6, 100 MHz, ambient T) δ (ppm): 170.7, 160.8, 126.1, 110.8, 110.6, 70.5, 70.3, 70.1, 68.8, 26.0 (10 peaks of 11 expected). Anal. Calcd: C 55.68, H 5.78; Found: C 55.74, H 5.66. N-Methyl-N,N-bis[N′-(5-carboxy-1,3-phenylene-16crown-5)propylamino]amine (3). A solution of N-methylN,N-bis(3-aminopropyl)amine (1, 19.0 mg, 0.133 mmol) and 2 (110 mg, 0.0268 mmol) in CH2Cl2 (ca. 4-5 mL) was stirred at room temperature for 24 h, whereupon ∼4 mL of 1 M NaOH was added and the mixture stirred for 1 h. The organic layer was washed with a concentrated sodium bicarbonate solution followed by deionized H2O and concentrated by rotoevaporation to give an oil. Yield: 105 mg (∼ 100%). 1H NMR (CDCl3, 300 MHz, ambient T) δ (ppm): 7.39 (2H, t, J ) 4.2 Hz), 7.20 (2H, d, J ) 2.1 Hz), 6.92 (4H, s), 4.29 (8H, t, J ) 4.8 Hz), 3.76 (8H, t, J ) 4.8 Hz), 3.60 (16H, m), 3.49 (4H, m), 2.50 (4H, t, J ) 6.3 Hz), 2.27 (3H, s), 1.78 (4H, t, J ) 6.3 Hz). 13C NMR (CDCl3, 75 MHz, ambient T) δ (ppm): 167.6, 160.8, 137.1, 109.2, 107.4, 71.3, 71.2, 70.9, 69.4, 57.4, 42.4, 40.0, 27.0 (13 peaks as required). EI-MS (acetone): m/z 734.5 (3 + H+) (calcd m/z 734.4), m/z 1468.0 {2 × [3 + H+]}(calcd m/z 1468.8). N-(2-Carboxydibenzo-24-crown-8)succinimide (4). 2-Carboxydibenzo-24-crown-86b (1.34 g, 2.73 mmol) and N-hydroxysuccinimide (0.323 g, 2.81 mmol) were dissolved in 50 mL of glyme. To this stirring solution was added dicyclohexylcarbodiimide (0.620 g, 3.00 mmol) at 0 °C, resulting in incomplete dissolution of the reactant species. The mixture was stirred for 48 h, whereupon the precipitate was filtered under vacuum and washed with CHCl3. The filtrate was dried to yield an oil, which was dissolved in hot isopropyl alcohol. Upon cooling, a white powder was obtained and purified by column chromatography (SiO2, 1. EtOH, 2. MeOH); 4 was recrystallized from isopropyl alcohol. Yield: 0.631 g, (39.2%). Mp ) 81-90 °C. 1H NMR (DMSO-d6, 400 MHz, ambient temp) δ (ppm): 7.71 (1H, d, J ) 8.8 Hz); 7.48 (1H, s); 7.71 (1H, d, J ) 8.8 Hz), 6.89 (4H, m); 4.21 (4H, m); 4.15 (4H, m); 4.05 (8H, m); 3.77 (16H, m); 3.66 (16H, m); 2.87 (4H, s). 13C NMR (DMSO-d6, 100 MHz, ambient temp) δ (ppm): 170.4, 161.3, 157.8, 154.3, 148.4, 148.3, 148.2, 124.8, 121.1, 116.2, 114.0, 113.9, 113.8, 112.8, 70.55, 70.47, 70.40, 69.2, 69.13, 69.0, 68.9, 68.74, 68.69, 68.66, 25.5. Anal. Calcd: C 59.11, H 6.08. Found: C 59.08, H 5.98. m-Phenylene-16-crown-5 Functionalized Dendrimers. m-Phenylene-16-crown-5 (MP16C5) functionalized PPI dendrimers were prepared using the same procedure described above for the synthesis of 3. DAB-dend-(CO-MP16C5)4.28 Yield: 117 mg (∼100%). 1H NMR (CDCl3, 300 MHz, ambient temp) δ (ppm): 7.31 (4H, m), 7.19 (4H, t, J ) 2.1 Hz), 6.92 (27) Nagvekar, D. S.; Delaviz, Y.; Prasad, A.; Merola, J. S.; Marand, H.; Gibson, H. W. J. Org. Chem. 1996, 61, 1211-1218. (28) Our crowned PPI dendrimers have been named according to convention (see ref 1c): the label DAB-dend-(X)y denotes a dendritic structure bearing a diaminobutane core surrounded by y endgroups of type X functionality. For example, DAB-dend-(CO2CH2BMP32C10)4 represents molecule 6, wherein a diaminobutane cored dendrimer has been functionalized at the periphery with four BMP32C10 macrocycles, which have been coupled to the PPI terminal groups by means of a CO2CH2 linker.

(8H, d, J ) 3.0 Hz), 4.26 (16H, t, J ) 4.8 Hz), 3.74 (16H, t, J ) 4.8 Hz), 3.58 (32H, m), 3.45 (8H, m), 2.48 (8H, m), 2.39 (4H, br s), 1.71 (8H, t, J ) 6.9 Hz), 1.40 (4H, br s). 13C NMR (CDCl3, 75 MHz, ambient temp) δ (ppm): 167.1, 160.3, 136.4, 108.7, 106.9, 70.7, 70.6, 70.3, 68.8, 53.9, 52.6, 39.3, 26.7, 24.8 (14 peaks as required). DAB-dend-(CO-MP16C5)16. Yield: 108 mg (∼100%). 1H NMR (CDCl3, 300 MHz, ambient temp) δ (ppm): 7.78 (16H, br s), 7.17 (16H, s), 7.03 (32H, s), 4.22 (64H, br s), 3.58 (224H, m), 2.38 (84H, m), 1.55 (60H, m). 13C NMR (CDCl3, 75 MHz, ambient temp) δ (ppm): 167.2, 160.2, 136.3, 108.9, 107.1, 70.7, 70.6, 70.2, 68.8, 52.1, 39.1, 30.9, 26.8, 24.5. DAB-dend-(CO-MP16C5)64. Yield: 86.5 mg (84.2%). 1H NMR (CDCl3, 300 MHz, ambient temp) δ (ppm): 8.11 (64H, br s), 7.12 (64H, s), 7.06 (128H, s), 4.15 (256H, br s), 3.55 (896H, m), 2.39 (376H, br s), 1.60 (252H, br s). 13C NMR (CDCl3, 75 MHz, ambient temp) δ (ppm): 167.3, 160.2, 136.2, 109.1, 70.6, 70.2, 68.8, 54.3, 52.5, 40.6, 31.3, 25.4. Bis(m-phenylene)-32-crown-10 Functionalized Dendrimers (6 and 7). BMP32C10-functionalized PPI dendrimers were prepared as described in the following typical procedure. The polyamine (114 mg) in CHCl3 (5 mL) was injected into a stirred CHCl3 solution (15 mL) of di-tert-butyltricarbonate (959 mg) and stirred at room temperature for 15 min under Ar. Formation of isocyanates was checked with IR spectroscopy (ν ) 2265 cm-1). Hydroxymethyl BMP32C1013 (1.00 g) and zirconium(IV) acetylacetonate (0.1 mol %) were added; after 16 h the reaction mixture was precipitated in ice-cold heptane (250 mL). After size exclusion chromatography (Bio-Beads SX-1 column, CH2Cl2) and solvent removal in vacuo, yellowish highly viscous oils 6 and 7 were obtained and characterized as described below. DAB-dend-(CO2CH2BMP32C10)4 (6). Yield: 860 mg (93%). 1H NMR (CDCl , 400 MHz, ambient temp) δ (ppm): 1.38 (4H, 3 br s), 1.60 (8H, br s), 2.34 (4H, br s), 2.40 (8H, br s), 3.18 (8H, q, J ) 6 Hz), 3.68 (64H, s), 3.81 (32H, quint, J ) 5 Hz), 4.04 (32 H, quint, J ) 5 Hz), 4.96 (8H, s), 5.68 (4H, br s), 6.40 (4H, s), 6.47 (20H, m), 7.11 (4H, t, J ) 8 Hz). 13C NMR (CDCl3, 100 MHz, ambient temp) δ (ppm): 25.1, 27.4, 40.3, 52.3, 53.8, 54.1, 66.5, 67.8, 69.9, 71.1, 101.1, 101.9, 106.8, 107.3, 129.9, 139.1, 156.5, 160.0. IR: νmax 3339 (w.br), 2926 (m), 2871 (m), 1713 (s), 1594 (s), 1494 (s), 1125 (s), 1067 (s) cm-1. MALDI-TOF MS m/z 2709 [M + Na]+. DAB-dend-(CO2CH2BMP32C10)16 (7). Yield: 362 mg (83%). 1H NMR (CDCl3, 400 MHz, ambient temp) δ (ppm) 1.36 (4H, br s), 1.44-1.64 (56H, br s), 2.28-2.44 (84H, br s), 3.103.18 (32H, br s), 3.60-3.64 (128H, br s), 3.72-3.80 (128H, br s), 3.96-4.06 (128 H br s), 4.92 (32H, s), 5.76-5.90 (16H, br s), 6.37 (H, br s), 6.40-6.48 (112H, m, br s), 7.09 (16H, t, J ) 8 Hz). 13C NMR (CDCl3, 100 MHz, ambient temp) δ (ppm) 24.2, 27.3, 39.8, 51.7, 52.2, 66.2, 67.6, 69.7, 70.8, 100.9, 101.8, 106.7, 107.2, 129.9, 139.1, 156.6, 160.0. IR: νmax 3339 (w.br), 2926 (m), 2870 (m), 1711 (s), 1594 (s), 1449 (s), 1125 (s), 1067 (s) cm-1. MALDI-TOF MS m/z 11167 [M + H]+.

Acknowledgment. We gratefully acknowledge J. L. J. van Dongen for the mass spectra; DSM Research, The Netherlands, for an unrestricted research grant (E.W.M.) and for the dendrimers; the Petroleum Research fund administered by the American Chemical Society (33518AC7, H.W.G.) as well as the National Science Foundation (grant DMR-0097126) for funding; and NATO for a Collaborative Research Grant funding travel between The Netherlands and the United States (SRG 960855, H.W.G. and R.A.J.J.). JO0265784

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